Epidermal growth factor receptor-inhibitors and radiotherapy-induced cutaneous adverse effects: “Koebner-Phenomenon” or radio-dermatitis?

Abstract

We have read with great interest the articles [ 1 Eriksen J.G. Overgaard M. Late onset of skin toxicity induced by EGFr-inhibitors. Radiother Oncol. 2009; 90: 280-281 Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar , 2 Giro C. Berger B. Bölke E. et al. High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: Results of a survey in EORTC Institutes. Radiother Oncol. 2009; 90: 166-171 Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar , 3 Pryor D.I. Porceddu S.V. Burmeister B.H. et al. Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. Radiother Oncol. 2009; 90: 172-176 Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar ] on the usage of epidermal growth factor receptor-Inhibitors (EGFRr-Is) and radiotherapy in Locally advanced Head and Neck cancer (LA-HNC). All these articles highlighted the severity of radio-dermatitis, concluding that its incidence may be higher in routine clinical practice than in the clinical trial by Bonner et al. [ [4] Bonner J.A. Harari P.M. Giralt J. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006; 354: 567-578 Crossref PubMed Scopus (4085) Google Scholar ]. We have observed similar cutaneous reactions in the AlteRCC trial (Alternating Radiotherapy and Chemotherapy plus Cetuximab in LA-HNC) [ 5 Merlano MC, Benasso M, Numico G. et al. Chemo-radiation (ctrt) and cetuximab (cmab) in locally advanced head and neck cancer (LA HNC). 33° ESMO meeting, Stockholm 2008. Ann Oncol 2008;19(Suppl. 8) [abstr. 694PD]. Google Scholar , 6 Russi E.G. Merlano M.C. Comino A. Numico G. Ultrathin hydrocolloid dressing in skin damaged from alternating radiotherapy and chemotherapy plus cetuximab in advanced head and neck cancer (G.O.N.O. altercc Italian trial). Int J Radiation Oncology Biol Phys. 2007; 69 ([letter]): 638-641 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar ] and we also agree with this statement. In our opinion the difference in incidence across the different studies [ 2 Giro C. Berger B. Bölke E. et al. High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: Results of a survey in EORTC Institutes. Radiother Oncol. 2009; 90: 166-171 Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar , 3 Pryor D.I. Porceddu S.V. Burmeister B.H. et al. Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. Radiother Oncol. 2009; 90: 172-176 Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar , 4 Bonner J.A. Harari P.M. Giralt J. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006; 354: 567-578 Crossref PubMed Scopus (4085) Google Scholar , 5 Merlano MC, Benasso M, Numico G. et al. Chemo-radiation (ctrt) and cetuximab (cmab) in locally advanced head and neck cancer (LA HNC). 33° ESMO meeting, Stockholm 2008. Ann Oncol 2008;19(Suppl. 8) [abstr. 694PD]. Google Scholar ] can be explained from the fact that this radio-dermatitis has different clinical expressions: severe folliculitis [ [3] Pryor D.I. Porceddu S.V. Burmeister B.H. et al. Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. Radiother Oncol. 2009; 90: 172-176 Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar ], acneiform rush [ [7] Mydin A.R. Armstrong J.G. Acneiform rash secondary to cetuximab plus head and neck radiotherapy. Radiother Oncol. 2007; 85: 171 Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar ], exulceration (dermatitis with complete loss of the epidermis [ [8] Budach W. Bölke E. Homey B. Severe cutaneous reaction during radiation therapy with concurrent cetuximab. N Engl J Med. 2007; 357: 514-515 Crossref PubMed Scopus (108) Google Scholar ]) all confined to the irradiation field and often complicated from an early crusty exudation on a xerotic and thin, easily bleeding cutis. Therefore, upon clinical inspection, it appears different from traditional radio-dermatitis, induced by radiation alone; this fact can also explain the difficulty in scoring its severity. In the first patients treated in the AlteRCC [ [6] Russi E.G. Merlano M.C. Comino A. Numico G. Ultrathin hydrocolloid dressing in skin damaged from alternating radiotherapy and chemotherapy plus cetuximab in advanced head and neck cancer (G.O.N.O. altercc Italian trial). Int J Radiation Oncology Biol Phys. 2007; 69 ([letter]): 638-641 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar ] trial, we often classified the major skin toxicity as G4–CTCAE v.3.0 [ [9] Common Terminology Criteria for Adverse Events v3.0 (CTCAE); 2006. p. 15. Available from: <http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf/ [last visited December 20, 2008]. Google Scholar ], because we were impressed from the red bloody crusty exudation that induced us to erroneously suppose a full thickness dermis necrosis with spontaneous bleeding. The rapid healing without scarring nor other sequelae, achieved within few days after treatment end, as well as the biopsy performed in one of these patients, directed us to re-classify this toxicity as G.-3 radio-dermatitis. Microscopy showed a thin epidermis, an atrophic basal stratum and an inflammatory lympho-plasmacellular and granulocytic infiltration of the subepidermis: only in “rare areas” could it be observed a limited necrosis of the epidermis and of the superficial dermis [ [6] Russi E.G. Merlano M.C. Comino A. Numico G. Ultrathin hydrocolloid dressing in skin damaged from alternating radiotherapy and chemotherapy plus cetuximab in advanced head and neck cancer (G.O.N.O. altercc Italian trial). Int J Radiation Oncology Biol Phys. 2007; 69 ([letter]): 638-641 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar ]. Notably, all the Authors [ 3 Pryor D.I. Porceddu S.V. Burmeister B.H. et al. Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. Radiother Oncol. 2009; 90: 172-176 Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar , 5 Merlano MC, Benasso M, Numico G. et al. Chemo-radiation (ctrt) and cetuximab (cmab) in locally advanced head and neck cancer (LA HNC). 33° ESMO meeting, Stockholm 2008. Ann Oncol 2008;19(Suppl. 8) [abstr. 694PD]. Google Scholar , 6 Russi E.G. Merlano M.C. Comino A. Numico G. Ultrathin hydrocolloid dressing in skin damaged from alternating radiotherapy and chemotherapy plus cetuximab in advanced head and neck cancer (G.O.N.O. altercc Italian trial). Int J Radiation Oncology Biol Phys. 2007; 69 ([letter]): 638-641 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar , 8 Budach W. Bölke E. Homey B. Severe cutaneous reaction during radiation therapy with concurrent cetuximab. N Engl J Med. 2007; 357: 514-515 Crossref PubMed Scopus (108) Google Scholar , 10 Bölke E. Gerber P.A. Lammering G. et al. Development and management of severe cutaneous side effects in head-and-neck cancer patients during concurrent radiotherapy and cetuximab. Strahlenther Onkol. 2008; 184: 105-110 Crossref PubMed Scopus (56) Google Scholar ] who describe similar cases report a completely healed skin without disfiguring scar in the damaged area.